Cancer is a leading cause of death worldwide and accounted for 7.6 million deaths (around 13% of all deaths) in 2008. Melanoma is an example of a cancer aligning the skin tissue surface and used here as an example. About 10% of all people with melanoma have a family history of melanoma. One is at increased risk of developing melanoma if there is a family history of melanoma in one or more of your first-degree relatives (parent, brother or sister, or child).
Melanoma is currently the sixth most common cancer in American men and the seventh most common in American women. The median age at diagnosis is between 45 and 55, although 25% of cases occur in individuals before age 40. It is the second most common cancer in women between the ages of 20 and 35, and the leading cause of cancer death in women ages 25 to 30.
Melanoma is the most aggressive form of skin cancer. If it is recognized and treated early it is almost always curable, but if it is not, the cancer can advance and spread to other parts of the body, where it becomes hard to treat and can be fatal. While it is not the most common of the skin cancers, it causes the most deaths. The American Cancer Society estimates that at present, about 120,000 new cases of melanoma in the US are diagnosed in a year. In 2010, about 68,130 of these were invasive melanomas, with about 38,870 in males and 29, 260 in women.
There are four basic types of melanoma which differ in frequency and location in the body. All melanomas pose the same level of risk, based on the following factors: Tumor depth (Breslow depth), Mitotic index (cells that are dividing within the melanoma), presence or absence of ulceration, number of regional lymph nodes containing melanoma, and extent of cancer spread in the regional lymph nodes.
Superficial spreading melanoma is the most common type of melanoma, representing about 70% of all cases. As its name suggests, it spreads along the epidermis for a period of months to years before penetrating more deeply into the skin. The melanoma appears as a flat or barely raised lesion, often with irregular borders and variations in color. Lesions most commonly appear on the trunks of men, the legs of women, and the upper back of both sexes. The earliest sign of a new superficial spreading melanoma is darkening in one part of a pre-existing mole or the appearance of a new mole on unaffected normal skin.
Nodular melanoma represents 15 to 30% of all melanomas. It grows deeper more quickly than other types of melanoma, and is found most often on the trunk or head and neck. The melanoma usually appears as a blue-black, dome-shaped nodule, although 5% of lesions are pink or red. Nodular melanoma is more common in men than women.
Lentigo maligna melanoma arises from a pre-existing lentigo, rather than a mole, and accounts for approximately 5% of all melanoma cases. This type of melanoma typically takes many years to develop. It occurs most often in older adults, usually on the face and other chronically sun-exposed areas. These melanomas are generally large, flat, tan-colored lesions containing differing shades of brown, or as in other melanomas, black, blue, red, gray, or white.
Acral lentiginous melanoma accounts for less than 5% of all melanomas but is the most common melanoma in African Americans and Asians; although this may also occur in light-skinned (Caucasian) individuals. The disease typically appears on the palms, soles, or under the nails. Lesions are usually tan, brown, or black, with variations in color and irregular borders. Because of the misconceptions that melanomas only occur in sun-exposed areas, and that dark-skinned and Asian people are not at risk for melanoma, these melanomas are often discovered later than other forms of melanoma. A tendency to mistake the early signs of acral lentiginous melanoma for bruises or injuries to the palms, soles, or nailbeds may further delay diagnosis.
Early detection of melanoma is critical for treatment and survival. When melanoma is found and treated early, the chances for long-term survival are excellent. Five-year survival rates for patients with early-stage (Stage I) melanoma exceed 90 to 95%. As melanoma progresses, it becomes increasingly more devastating and deadly. In later-stage disease, 5-year survival rates drop to less than 85%. With early detection, survival rates have improved steadily in recent years, and 85% of diagnosed patients enjoy long-term survival after simple tumor surgery.
The first sign of melanoma is often a change in the size, shape, or color of an existing mole or the appearance of a new mole. Since the vast majority of primary melanomas are visible on the skin, there is a good chance of detecting the disease in its early stages. However, changes in size, shape, or color of an existing mole or the appearance of a new mole is not always conclusive of presence of melanoma in a mole. Men most commonly develop melanoma on the trunk, particularly the back, and women on the legs or arms.
If the primary care physician suspects one may have melanoma, one will be referred to a dermatologist, a medical oncologist, or a surgical oncologist. To make a definitive diagnosis, they will perform examinations and tests. The doctor will first take a complete medical history to learn about ones symptoms and risk factors. Your age, time since your first concern, changes in features, sun burns, family history of atypical moles or skin cancer, particularly melanoma. Complete skin examination. Dermoscopy, Biopsy, Lymph node examination, chest x-ray, CT scan, Magnetic resonance imaging (MRI), Serum lactate dehydrogenase (LDH).
Melanoma is staged is based on the risk factors most important in determining prognosis. They include: Tumor thickness (also known as Breslow thickness): how deeply the tumor has penetrated the skin. Thickness is measured in millimeters (mm). Thinner tumors carry a more favorable prognosis than thicker tumors. The thicker the tumor, the greater the risk of tumor metastasis. The presence or absence of tumor ulceration: A condition in which the epidermis that covers a portion of the primary melanoma is not intact. Ulcerated tumors pose a greater risk for metastatic disease than tumors that are not ulcerated. Mitoses: Active cell division of the tumor and can be defined in terms of number. This is determined by the pathologist. The more mitoses, the more aggressive the tumor growth. Metastatic lymph nodes. The greater the number of lymph nodes containing melanoma, the less favorable the prognosis. Whether metastasis to the lymph nodes is microscopic or macroscopic. Micrometastases are tiny tumors. They can be detected only by microscopic evaluation after sentinel lymph node biopsy or elective lymph node dissection. Macrometastases can be felt during physical examination or seen by the naked eye when inspected by a surgeon or pathologist. Their presence is confirmed by lymph node dissection or when the tumor is seen to extend beyond the lymph node capsule. Macrometastases carry a less favorable prognosis than micrometastases. The site of distant metastasis. Distant metastases to the skin, the subcutaneous tissue, or distant lymph nodes carry a relatively better prognosis than distant metastases to any other site in the body. Level of serum lactate dehydrogenase (LDH). LDH is an enzyme found in the blood and many body tissues. Elevated LDH levels usually indicate the presence of metastatic disease—and a less favorable prognosis than normal LDH levels.
The TNM Staging System was created by the American Joint Committee on Cancer (AJCC). The system defines cancer stage by describing:    T: the features of the primary tumor. The three distinguishing features are tumor thickness, mitoses, and ulceration. Tumor thickness (also known as Breslow depth) is measured in millimeters (mm).    N: the presence or absence of tumor spread to nearby lymph nodes    M: the presence or absence of metastasis to distant sitesRevised TNM ClassificationAbbreviations: N/A, not applicable; LDH, lactate dehydrogenases.
T ClassificationThicknessUlceration StatusTisN/AN/AT1≤1.0 mma: w/o ulceration and mitosis <1/mm2b: with ulceration and mitosis ≥1/mm2T21.01-2.0 mma: w/o ulcerationb: with ulcerationT32.01-4.0 mma: w/o ulcerationb: with ulcerationT4>4.0 mma: w/o ulcerationb: with ulcerationN Classification# of Metastatic NodesNodal Metastatic MassN0No evidence of lymph node metastasisN11 nodea: micrometastasisb: macrometastasisN22-3 nodesa: micrometastasisb: macrometastasisc: In transit metastases/satelliteswithout metastatic nodesN34 or more metastatic nodes, or matted nodes, or in-transitmetastases/satellites and metastatic nodesM Classification SiteSerum LDHM0No evidence of metastasis to distant tissues or organsM1aDistant skin, subcutaneous orNormalnodal metastasesM1bLung metastasesNormalM1cAll other visceral metastasesNormalOr any distant metastasesElevated
One of the most important factors in staging melanoma—and in determining treatment and prognosis—is how deeply the tumor has penetrated the skin. Tumor depth is described in two ways: Breslow thickness is a method of measuring how deeply the primary tumor has penetrated the skin, regardless of anatomic layer. Tumor penetration is measured in millimeters (mm) from the epidermis to the deepest point of penetration. (1.0 mm=0.04 inch, or less than 1/16 inch.) Breslow thickness has replaced Clark level as a more accurate measurement of tumor depth and more predictive of prognosis. The thicker the tumor, the greater the chance it has metastasized to regional lymph nodes or distant sites.
Clark level is a method of measuring how deeply the primary tumor has penetrated the skin based on anatomic layer. The deeper the layer of penetration, the greater the chance the tumor has metastasized to regional lymph nodes or distant sites. Since skin thickness varies throughout the body, Clark level is considered to be less accurate than Breslow thickness in describing tumor penetration. In fact, in the new American Joint Committee on Cancer (AJCC) staging system for melanoma, Clark level is no longer considered a secondary characteristic of Stage I tumors no more than 1.0 mm thick. This has been replaced with mitoses.
Clark level I. The tumor is located only in the lowest layer of the epidermis, known as the dermo-epidermal junction. Level I is also known as melanoma in situ. Clark level II. The tumor has partially penetrated the papillary dermis, the loose connective tissue beneath the epidermis. Clark level III. The tumor has completely penetrated and filled the papillary dermis. Clark level IV. The tumor has penetrated through the papillary dermis to the dense connective tissue of the reticular dermis. Clark level V. The tumor has penetrated through the reticular dermis to the subcutaneous tissue, the fatty layer beneath the skin.
Melanoma is now grouped into the following stages according to the revised TNM staging system:
Stage 0 melanoma involves the epidermis but has not reached the underlying dermis.
This stage is also called melanoma in situ (TisN0M0). Stage 0 melanoma is very early stage disease known as melanoma in situ (Latin for “in place”). Patients with melanoma in situ are classified as Tis (tumor in situ). The tumor is limited to the epidermis with no invasion of surrounding tissues, lymph nodes, or distant sites. Melanoma in situ is considered to be very low risk for disease recurrence or spread to lymph nodes or distant sites.
Stage I melanoma is characterized by tumor thickness, presence and number of mitoses, and ulceration status. There is no evidence of regional lymph node or distant metastasis.
There are two subclasses of Stage I melanoma.
Stage IA: T1aN0M0 (tumor less than or equal to 1 mm, no ulceration, and no mitoses). Stage IB: T1bN0M0 or T2aN0M0 (tumor less than or equal to 1 mm, with ulceration or mitoses).
Stage I melanomas are localized tumors. This means the primary tumor has not spread to nearby lymph nodes or distant sites. Stage I melanomas are considered to be low-risk for recurrence and metastasis.
Stage I melanomas are defined by two primary characteristics:
Tumor thickness (known as Breslow depth): how deeply the tumor has penetrated the skin. Thickness is measured in millimeters (mm). Ulceration: a condition in which the epidermis that covers a portion of the primary melanoma is not intact. Ulceration is determined by microscopic evaluation of the tissue by a pathologist, not by what can be seen with the naked eye. Mitoses: A condition of the cells being in a state of active division. Mitoses are determined by microscopic evaluation by a pathologist, not what can be seen with the naked eye, similar to ulceration. It will be defined as “present or not present” and should include a number of mitoses per mm 2. The designation of Clark level measures the depth of invasion according to the number of layers of skin the tumor has penetrated. There are five anatomic layers of the skin: Level I: epidermis. Levels II-IV: dermis. Level V: the subcutis.
Clark level is no longer considered by the new American Joint Committee on Cancer (AJCC) staging system for melanoma, as a secondary characteristic of Stage I tumors no more than 1.0 mm thick. This has been replaced with mitoses.
Subclasses of Stage I Melanoma
Stage IA (T1aN0M0) T1a: the tumor is no more than 1.0 millimeter (mm) thick, with no ulceration and no mitoses. NO: the tumor has not spread to nearby lymph nodes. M0: the tumor has not spread to sites distant from the primary tumor. Stage IB (T1bN0M0 or T2aN0M0). T1b: the tumor is no more than 1.0 mm thick, with ulceration or presence of >1 mitoses. T2a: the tumor is 1.01-2.0 mm thick, with no ulceration. N0: the tumor has not spread to nearby lymph nodes. M0: the tumor has not spread to sites distant from the primary tumor.
Stage II melanoma is also characterized by tumor thickness and ulceration status. There is no evidence of regional lymph node or distant metastasis.
There are three subclasses of Stage II melanoma.
Stage IIA: T2bN0M0 or T3aN0M0
Stage IIB: T3bN0M0 or T4aN0M0
Stage IIC: T4bN0M0
Stage III melanoma is characterized by the level of lymph node metastasis. There is no evidence of distant metastasis.
There are three subclasses of Stage III melanoma.
Stage IIIA: T1-T4aN1aM0 or T1-T4aN2aM0
Stage IIIB: T1-T4bN1aM0, T1-T4bN2aM0, T1-T4aN1bM0, T1-T4aN2bM0, or T1-T4a/bN2cM0
Stage IIIC: T1-4bN1bN0, T1-4bN2bM0, or T1-4a/bN3M0
Stage IV melanoma is characterized by the location of distant metastases and the level of serum lactate dehydrogenase (LDH).
Stage IV melanomas include any T or N classification. For details, see Stage IV.
Treatments are available for all people with melanoma. In many cases, the standard treatment is surgery to remove the tumor and a surrounding area of normal-appearing skin. Sometimes surgery is followed by additional therapy such as immunotherapy, chemotherapy, radiation, or a combination of these treatments. Chemotherapy and immunotherapy are also used to treat advanced or recurrent melanoma.
Tumors need blood flow to grow bigger than 2-3 mm. Judah Folkman first articulated the importance of angiogenesis for tumor growth in 1971. He stated that the growth of solid tumors remains restricted to 2-3 mm in diameter until the onset of angiogenesis. Tumors need oxygen and nutrients. For the first 2 mm of their growth (˜one million cells) tumors get their oxygen and nutrients from the host capillaries and extracellular fluid. As they outgrow the host supply they start making their own blood vessels. Cancers “persuade” the existing host capillaries to sprout, change direction and grow throughout the tumor. To do this, they secrete growth factors—angiogenic factors.
Angiogenesis (neoangiogenesis) is a multistep process, which is regulated by a balance between pro- and antiangiogenic factors. Microtumor foci remain dormant until a biological event occurs to trigger growth beyond the 2 mm stage/size. One trigger is an insufficient nutrient supply resulting in hypoxic cells. State-of-the-art clinical PET scanners, are able to detect tumor foci with a resolution of 3-4 mm. Preclinical animal scanners allow for resolutions in the 1 mm range in small rodents.
Vascularization in melanoma occurs and melanoma becomes metastatic (>0.75 mm). Human malignant melanoma is a highly metastatic tumor with poor prognosis and high resistance to treatment. It progresses through different steps: nevocellular nevi, dysplastic nevi (when these two entity can be identified as primary events in melanocytic neoplasia progression), in situ melanoma, radial growth phase melanoma (Breslow index ≤0.75 mm), vertical growth phase melanoma (index >0.75 mm), and metastatic melanoma. Breslow's depth is used as a prognostic factor in melanoma of the skin. It is a description of how deeply tumor cells have invaded. Melanomas in the vertical growth stage phase are metastatic.
Primary melanoma tumor grows horizontally through the epidermis (non-invasive phase); over time, a vertical growth phase component intervenes and melanoma increases its thickness and invades the dermis (invasive phase). Once a vertical growth phase has developed, there is a direct correlation between the tumor thickness and the number of metastases.
Blood flow occurs in melanoma index >0.8 mm. To correlate melanoma thickness and angiogenesis, the blood flow in 71 primary skin melanomas were investigated using a 10 MHz Doppler ultrasound flowmeter. Flow signals were analyzed on an Angioscan-II spectrum analyzer. Doppler flow signals were detected in 44 tumors, with a close relationship to Breslow's tumor thickness. No blood flow signal was detected in 27 lesions and 25 of these had a tumor thickness of 0.8 mm or less. Ninety-seven percent of tumors of thickness >0.8 mm had detectable Doppler flow signals. This study indicates the development of a neovascular bed as the tumor thickness approaches 0.8 mm. An additional study of tumor blood flow in 36 patients, 38 with malignant melanomas using Doppler Ultrasound flowmetry showed that tumor blood flow can be detected in most melanomas more than 0.9 mm thick, and is absent in most melanomas less than this thickness.
Cancer starts in a single cell. Cells accumulate genetic changes and become abnormal. During the early stages of tumor development first a micro tumor lesion is formed. At the second stage a tumor lesion is formed which expands beyond the size of the micro lesion. In the final stage tumor cells are released to the circulatory system in the process of metastasis.
Tumors remain dormant as microfoci in the body. At the stage of a micro tumor lesion, signals from the immune system can hold a micro tumor in check in a state of tumor dormancy by the tumor inability to grow beyond it's local macroenvironment. In this state, the level of cell proliferation is in balance to the level of cell death. As tumors accumulate additional genetic changes, they are able to disrupt this balance and grow beyond microfoci and the macroenvironment. This balanced state is overturned when the signals originating from the tumor increase overpowering the signals from the immune system. Tumor cells secret signaling proteins to the tumor microenvironment and macroenvironment. During this stage emerging tumors signal to the macroenvironmet the need, to expand into additional space and additional nutrient as well as oxygen required for expanded growth. These signals prepare the tumor environment for expanded tumor growth (increasing space) and for an increase in nutrient supply (angiogenesis). The process is mediated by growth factors, cytokines and other activations proteins released from the tumor cells or from the tumor macro/micro environment during tumor expansion.
These processes can be investigated by testing the tissue surrounding a tumor (macro environment-tissue surrounding the diseased tissue). Often this environment may be difficult to study, especially if the tumor is embedded deep in a tissue. However, tumor growths in the proximity of the tissue cavity/surface compartment are good candidates to this type of investigation. Examples of such tumors can be: skin cancers, mouth cancer, lung cancer, colon cancer, digestive system cancer, cervical cancer, bladder cancer, etc.
The ideal medical diagnostic procedure and tools would have the following characteristics: is minimally invasive or non-invasive; permits early stage disease detection; permits early body response to a new antigen; permits early body response to a foreign antigen, monitors disease development and progression; investigates the macro environment of the diseased cell and/or tissue as indication of presence of disease; is easy to use, low cost, provides a quick test to perform; can be performed by someone other than the physician; operates independent of skin color or ethnicity; provides immediate test results, provides consistency of results, works for a wide range of lesion types and body locations; is minimally dependent on human interpretation; is a simple test—minimal training necessary; provides automated or machine-assisted medical documentation, such as photographs or quantified test metrics; provides automated or machine-assisted electronic medical record keeping, such as machine readable codes on samples and files that directly tie to patient, doctor and date; operates independent of visual cues such as, color, shape and size; can identify melanoma in amelanotic skin lesion; and/or can identify melanoma in small lesions, less than 5 mm. Current technology has weaknesses in all or some of the above areas.
Also, the prior art uses an industrial camera connected to a computer. This arrangement is either impossible to hand hold, is too cumbersome to realistically handhold, or is difficult to consistently place in the correct position.
Prior art uses a fixed focal length lens, which only works when the camera can be placed a fixed distance from the subject. When using fluorescent biomarkers it is preferable to block all ambient and stray light from entering the optical path between the camera optics and the patient's skin. Therefore, some kind of physical light shield or light baffle is employed. This light baffle is normally affixed to the camera, surrounding the lens with an approximately pyramidal or conical shape, with the truncated point of the pyramid/cone being at the camera and the base of the pyramid/cone against the patient's skin. This approach is sometimes adequate for relatively flat or convex areas of skin, such as on a patient's back. The fixed focal point of prior art is fixed at the distance of the base of the pyramidal light shield. However, arrangement fails for some lesion locations, such as on the side of a patient's nose where the light baffle will not block the ambient or stray light.
Such art can include one or more of the following: Balch et al. J Clin Oncol 2001; 19:3635-3648; Folkman, J. (1971). New England Journal of Medicine, 285, 1182-1186; Folkman J, Klagsbrun M. In: Gottlieb A A, Plescia O J, Bishop D H L, eds. Fundamental Aspect of Neoplasia. Berlin, Springer, 1975, 401-412; Ellis, et al. (2002). Oncology, 16, 14-22; Carmeliet, P., & Jain, R. K. (2000). Nature, 407, 249-257; Matsumoto et al. (2006). Performance characteristics of a new 3-dimensional continuous emission and spiral-transmission high sensitivity and high resolution PETcamera evaluated with the NEMA NU 2-2001 standard. Journal of Nuclear Medicine, 47, 83-90; Chatziioannou, A. F. (2005). Instrumentation for molecular imaging in preclinical research: Micro-PET and Micro-SPECT. Proceedings of the American Thoracic Society, 2, 533-536; Breslow, Annals of Surgery, vol. 172, no. 5, pp. 902-908, 1970; Heasley, S. Toda, and M. C. Mihm Jr., Surgical Clinics of North America, vol. 76, no. 6, pp. 1223-1255, 1996; Srivastava A, Hughes L E, Woodcock J P, Laidler P. Vascularity in cutaneous melanoma detected by Doppler sonography and histology: correlation with tumour behaviour. Br J Cancer. 1989 January; 59(1):89-91; Srivastava A, Laidler P, Hughes L E, Woodcock J, Shedden E J: Neovascularization in human cutaneous melanoma: A quantitative morphological and Doppler ultrasound study. Eur J Cancer Clin Oncol 1986, 22:1205-1209, which are hereby incorporated by reference in their entirety.